L-carbethoxy-x-methylpiperazlisfe



Patented June 7, 1949 1-CARBETHOXY-4-METHYLPIPERAZINE,lTs

SALTS, AND METHOD or rnarnnnvq I,

SAME

Hugh W. Stewart, Plainfield, N.

1., assignor to American Cyanamid Company, New York, N. Y.,

a corporation of Maine I No Drawing. Application February 26, 1948, Serial No. 11,337

5 Claims.

This invention relates to new organic compounds and the methods of preparing the same. More particularly, the invention relates to 1- carbethoxy--methylpiperazine, its salts and methods of preparing said compounds.

In medical science there has long existed a need for compounds effective in the treatment of filariasis. In the past this disease has been treated with heavy metal organic com-pounds which, while being effective to some extent, must be used over a long period of time and have the relatively high toxicity characteristic of heavy metals in general. In a search ior compounds efi'ective in the treatment of filariasis, compounds of the type 1-carbethoxy-4-alkylpiperazine were prepared and tested. The compound l-carbethoxy-4-ethylpiperazine is known, having been described in the literature by Moore et :aL, Journal of the Chemical Society, 39 (1929). This compound, when tested against filariasis in the cotton rat, proved to be only slightly active.

I have found, unexpectedly, that the compound 1-carbethoxy-4-methylpiperazine shows a high degree of effectiveness against filariasis. This activity is unusual because the activity of adjacent homologues such as l-carbethoxyl-ethylpiperazine shown in the reference above, was of a very low order. I

The compounds of this general group may be illustrated by the following formula:

in which R is hydrogen or an alkyl radical. The relative activity of a number of these compounds is shown in the following table:

Minimum eiiective dose against micro- When B of the General formula is: filariae in the tonrat MgJKg. 25.0 (I. P.) 6.25 (LP) 50.0 (I. P.) 25.0 (1.1.) 25.0 (I.P.) 50.0 (1.1 100.0 oral inactive 200.0 oral inactive slightly above that of the compound shown in the reference. The compound 1-carbethoxy-4- methylpiperazine is approximately eight times as efiective as that of l-carbe-thoxyl-ethylpiperazine and at least four times more effective than any of the other compounds mentioned above. This high order of activity of the compounds of the present invention permits the obtaining of a therapeutic efiect at a much lower dosage level, which in turn lessens the possibility of toxicity.

The new 1-carbethoxy-4-methylpiperazine may be prepared by reacting l-carbethoxypiperazine or one of its salts with formaldehyde in a minera1 acid such as hydrochloric acid and in the resence of zinc. The reaction is generally carried out in water or aqueous solutions of solvents such as dioxane, ethanol, and the like.

It is preferred that the reaction be carried out at a temperature below 0., preferably from about 0 to 25 C.

The preparation and description of the hydrochloride salt is given hereinafter. Other salts of 1-carbethoxyl-methylpiperazine such as the hydrochloride, sulfate, dihydrogen citrate and the like, can be prepared in a similar manner.

To illustrate the invention with greater exactness the following description is given in which the new product is prepared from known intermediates. It will be understood, of course, that variations in the details may be made without departing from the initial features of the process.

To a solution of 106 parts of I-carbethoxypiperazine hydrochloride in 200 parts of water is added '72 parts of zinc dust. With cooling and stirring, 63.5 parts of 36% aqueous formaldehyde is slowly added, keeping the temperature at 15 C. Then, while maintaining a temperature of 15 C. by cooling, slowly add with stirring 240 parts of 38% aqueous hydrochloric acid. The reaction is then stirred overnight at room temperature. The small amount of zinc present is removed by filtration and to the filtrate slowly add, while stirring and cooling, 50% aqueous sodium hydroxide solution at 20 C. until the first precipitate of zinc hydroxide re-dissolves, giving a turbid solution. The oil which separates is extracted with ether and dried over sodium sulfate. On distillation at 7 mm., the yield is parts (96%) of 1-carbethoxy-4-methylpiperazine which distills at 9697 C. and is soluble in water.

By dissolving the 1-carbethoxy-4-methylpiperazine' in absolute ethanol and passing in dry hydrogen chloride, 1-carbethoxy-4-methylpipera 5. A method of preparing 1-carbethoxy-4-methylpiperazine which comprises mixing under reactive conditions a member of the group consisting of l-carbethoxypiperazine and salts thereof with formaldehyde in the presence of a mineral acid and zinc.

HUGH W. STEWART.

No references cited. 

